Leishmania are intracellular protozoan parasites which cause debilitating disease in many areas of the world. Infection of mice with Leishmania represents a good experimental model for the study of the interactions between the host and intracellular pathogens. In both man and mouse, specific T cell mediated responses are central for the immune defense against infection with Leishmania major. Recovery from natural or experimental infection leads to acquired immunity to reinfection, indicating that the control of leishmaniasis by prophylactic immunization is feasible. The immune response to primary infections with L major is well characterized. However, the mechanisms activated during reinfection have not been well investigated. The generation of long-term immunological memory is essential for the development of vaccines against infectious organisms. The rapid recognition and activation of parasitized macrophages by antigen-specific memory cells is crucially important for the maintenance of immunity to reinfection. The identification of those T cell functions necessary for the immunological control of leishmaniasis will depend upon the characterization of the T cell involved in the recall, or memory, response. The long term objective of the proposed study is to characterize the specific cells triggered in the immune host during the early phase of reinfection and the mechanisms by which they act in order to gain a better understanding for the complex interactions necessary to mount a protective response against reinfection. Therefore, resistant CBA and susceptible BALB/c mice, enabled to overcome their non-healing phenotype by various immuninterventions, will be infected with L major and allowed to recover fully from the primary infection. The immune response of these mice to secondary infectious challenge will then be analyzed. The kinetics of appearance, activation and function of CD4+ and CD8+ will be closely monitored during this process. It will be determined whether different T cell-mediated mechanisms contribute to the initial acquisition of Immunity to L. major and the subsequent resistance to rechallenge. The role of endogenous IFN-gamma during reinfection as well as the cells producing it will be determined by depletion experiments in vivo. Special emphasis will be placed on the contribution of Leishmania- specific CD8+ T cells to the IFN-gamma produced during reinfection. The MHC-restriction, antigen recognition and effector functions of the specific CD8+ T cells will be characterized in greater detail. The proposed contribution of CD8+ T cells to the redirection of the immune response of highly susceptible BALB/c mice, resistant by injection of low doses of promastigotes will be investigated (Bretscher et al., 1992).